TSHR Gene (rs179247) Polymorphism and Susceptibility to Autoimmune Thyroid Disease: A Systematic Review and Meta-Analysis
Article information
Abstract
Background
Both Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are classified as autoimmune thyroid diseases (AITDs). It has been hypothesized that changes in the thyroid-stimulating hormone receptor (TSHR) gene may contribute to the development of these conditions. This study aimed to analyze the correlation between the TSHR rs179247 gene polymorphism and susceptibility to AITD.
Methods
We conducted a thorough search of the Google Scholar, Scopus, Medline, and Cochrane Library databases up until March 2, 2024, utilizing a combination of relevant keywords. This review examines data on the association between TSHR rs179247 and susceptibility to AITD. Random-effect models were employed to assess the odds ratio (OR), and the findings are presented along with their respective 95% confidence intervals (CIs).
Results
The meta-analysis included 12 studies. All genetic models of the TSHR rs179247 gene polymorphism were associated with an increased risk of developing GD. Specifically, the associations were observed in the dominant model (OR, 1.65; P<0.00001), recessive model (OR, 1.65; P<0.00001), as well as for the AA genotype (OR, 2.09; P<0.00001), AG genotype (OR, 1.39; P<0.00001), and A allele (OR, 1.44; P<0.00001). Further regression analysis revealed that these associations were consistent regardless of the country of origin, sample size, age, and sex distribution. However, no association was found between TSHR rs179247 and the risk of HT across all genetic models.
Conclusion
This study suggests that the TSHR rs179247 gene polymorphism is associated with an increased risk of GD, but not with HT, and may therefore serve as a potential biomarker.
INTRODUCTION
Autoimmune thyroid disease (AITD) encompasses a range of clinical disorders that affect the thyroid gland due to an autoimmune process in which the immune system mistakenly targets thyroid gland cells [1]. AITD includes two forms of thyroid disorders with distinct clinical presentations: Graves’ disease (GD) leads to hyperthyroidism, while Hashimoto thyroiditis (HT) results in hypothyroidism [1]. In GD, B lymphocyte cells produce thyroid-stimulating immunoglobulin, which binds to the thyroid-stimulating hormone receptor (TSHR) on the thyroid gland, leading to the secretion of thyroid hormone and the symptoms of hyperthyroidism [1,2]. GD is the primary cause of hyperthyroidism, accounting for about 60% to 80% of all cases of thyrotoxicosis worldwide [1,2]. In HT, lymphocyte cells, including T cells and B cells, infiltrate the thyroid gland, causing damage and eventually leading to hypothyroidism due to decreased thyroid hormone synthesis [1,3]. Like GD, HT is a common cause of hypothyroidism [1,3].
Globally, the estimated prevalence of GD is approximately 1% to 1.5% of the population, with an annual incidence of 20 to 30 cases per 100,000 people. This number is expected to continue rising [4]. The detrimental effects of GD should not be underestimated [5]. Research indicates that individuals with GD face a 23% higher risk of all-cause mortality than healthy individuals [5]. Meanwhile, HT has a worldwide prevalence of 10% to 12% and an annual incidence of 0.3 to 1.5 cases per 1,000 people [6]. Both GD and HT continue to impose a significant burden on society.
The mechanisms underlying why certain individuals are more susceptible to developing AITD remain elusive [7]. Like other diseases, both genetic and environmental factors can influence an individual’s vulnerability to AITD [7]. Studies have suggested that genetic factors account for approximately 70% to 80% of the susceptibility to AITD, while environmental factors account for the remaining 20% to 30% [7]. These genetic factors are divided into immune regulatory genes and thyroid-specific genes [8]. Among the thyroid-specific genes, the TSHR gene has been extensively studied for its link to AITD [8]. Genomewide association studies have identified significant associations between TSHR and major histocompatibility complex class II polymorphisms, consistently correlating with thyrotropin receptor antibody positivity and GD [9,10]. Consequently, it is hypothesized that the cleavage of the A subunit from TSHR may trigger the production of thyroid-stimulating antibodies, potentially leading to the onset of GD [9,10]. Previous research has shown that intronic polymorphisms are particularly intriguing due to their possible role in regulating TSHR expression [11]. Polymorphisms in intronic regions, such as rs179247, may influence the generation of short RNAs and provide multiple start sites for alternative mRNA transcription, which could affect gene expression or posttranslational modifications [11]. However, the link between TSHR gene polymorphism (rs179247) and AITD susceptibility remains unclear and a matter of debate. The aim of this study was to comprehensively investigate the relationship between TSHR gene polymorphism (rs179247) and susceptibility to AITD, encompassing both GD and HT.
METHODS
Eligibility criteria
The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline was selected as the standard for reporting in this review (Supplemental Table S1) [12]. The protocol of this review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD 42024520343). To be eligible for our study, studies were required to follow a case-control design, with participants consisting of patients diagnosed with AITD, specifically GD or HT (as the case group), and healthy individuals (as the control group). The research was also required to include data regarding TSHR gene polymorphisms, particularly rs179247, which can manifest as major (A) and minor (G) alleles, along with the distribution of genotype variants (AA, AG, and GG) in both patient groups.
Furthermore, we excluded the following studies: (1) research involving individuals with thyroid disorders other than AITD; (2) studies without a control group; (3) studies with limited information on rs179247; (4) studies not available in full-text format; and (5) studies employing methodologies other than the case-control design.
Search strategy and study selection
A thorough literature search was conducted across four international databases: Google Scholar, Scopus, Medline, and Cochrane Library, up until March 6, 2024. The search employed specific keywords: “(Autoimmune thyroid disease OR AITD OR Graves’ Disease OR GD OR Graves’ hyperthyroidism OR Basedow disease OR Hashimoto Thyroiditis OR HT OR Hashimoto’s disease OR autoimmune thyroiditis) AND (thyroid stimulating hormone receptor gene OR TSHR gene OR rs179247).” Two authors independently performed an initial screening of these databases using the aforementioned keywords. Additionally, they verified the citations exported to the reference manager to ensure their consistency and completeness. Citation tracking was utilized to identify additional relevant papers, which involved reviewing the references of the initially identified research, following citations, and exploring related articles. Two authors independently reviewed the titles and abstracts, excluding those that were not relevant to the study. Subsequently, the same two authors assessed the eligibility of the studies based on the full texts, resolving any discrepancies through discussion.
Data extraction
Two authors separately collected data from the eligible articles, such as participant characteristics (age and sex distribution) and study details (author’s last name, publication year, country, Hardy-Weinberg equation [HWE] testing, the genotyping method, and the number of participants).
Risk of bias assessment
Two authors independently evaluated each publication for potential bias using standardized tools. The Newcastle-Ottawa Scale (NOS) was employed to assess the overall quality of each observational study [13]. This scale measures the selection of study subjects, the comparability of participant groups, and the outcomes of the studies [13]. The scoring range of the instrument is from 0 to 9 [13]. Studies achieving a total score of 7 or higher were considered to be of good quality [13].
Statistical analysis
The outcomes, expressed as dichotomous variables, were calculated using odds ratios (ORs) with 95% confidence intervals (95% CIs), employing the Mantel-Haenszel technique. This approach facilitated the comparison of the TSHR (rs179247) gene polymorphism between two patient groups. Due to expected substantial heterogeneity stemming from variations in population characteristics, a random-effect model was used. The study included three common genetic models—dominant, recessive, and allele type—as well as three additional genotype models (AA vs. GG, AA vs. AG, and AG vs. GG). These models were used to thoroughly assess the association between the TSHR (rs179247) gene polymorphism and susceptibility to AITD. We used the I-squared (I2) statistic to evaluate heterogeneity among studies [14]. I2 values were categorized as ≤25%, 26%–50%, and >50%, indicating low, moderate, and high heterogeneity, respectively [14]. Meta-regression with a random-effects model was conducted using a restricted-maximum likelihood approach for pre-specified variables, including country of origin, sample size, mean age, and sex distribution. This analysis aimed to explore the interaction effects between TSHR gene polymorphism and these variables on the risk of AITD. A publication bias analysis was performed when at least 10 studies were available for each outcome of interest. Statistical analyses were carried out using Review Manager 5.4, a software developed by the Cochrane Collaboration (London, UK), and Comprehensive Meta-Analysis version 3 (Biostat, Englewood, NJ, USA).
Ethics approval
This was a systematic review and meta-analysis. The Faculty of Medicine, University of Syiah Kuala Research Ethics Committee confirmed that no ethical approval was required.
RESULTS
Study selection and characteristics
We searched four databases: Google Scholar (n=129), Scopus (n=13), Medline (n=12), and Cochrane Library (n=8). In total, we identified 162 citations. After removing 136 duplicates and ineligible citations based on title/abstract screening, we examined 26 records. Of these, 14 papers were excluded for the following reasons: eight were review articles, two had incomplete data for analysis, two lacked a control group, one had missing data on the outcomes of interest, and one was an abstract-only article. The list of excluded studies is available in Supplemental Table S2. The final selection included 12 papers [15-26] involving 8,594 patients with GD, 536 individuals with HT, and 8,543 healthy controls (Fig. 1). Among these studies, six originated from China, two from Japan, and one each from Brazil; Poland, the United Kingdom (UK), and a combined effort from the UK and Poland. The sample sizes varied, with the GD group ranging from 112 to 2,504, the HT group from 57 to 230, and the healthy control group from 56 to 2,784 across the studies reviewed. Most studies employed TaqMan real-time polymerase chain reaction for genotyping, with one exception that used matrix-assisted laser desorption/ionization coupled to time-of-flight mass spectrometry genotyping. Table 1 provides a comprehensive overview of the baseline parameters for each paper analyzed.
Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) diagram showing the detailed process of study selection for inclusion in the systematic review and meta-analysis.
Characteristics of the Included Studies
Quality of study assessment
All case-control studies included in our analysis were of high quality, scoring between 8 and 9 on the NOS, as shown in Table 2. Each study met the criteria for inclusion in the meta-analysis.
Quality Assessment of Observational Studies Using the Newcastle-Ottawa Scale
Graves’ disease
Classical model
1) Dominant (AA+AG vs. GG)
Our pooled analysis of datasets from 12 studies, encompassing 16,570 participants, demonstrated that the dominant model of TSHR gene polymorphism (rs179247) (AA+AG vs. GG) is associated with an increased risk of developing GD (OR, 1.65; 95% CI, 1.51 to 1.80; P<0.00001; I2=0%; random-effect model) (Fig. 2A).
Forest plot demonstrating the association between classical genetic models of the relationship between the thyroid-stimulating hormone receptor (TSHR) rs179247 gene polymorphism and the risk of Graves’ disease: (A) dominant (AA+AG vs. GG), (B) recessive (AA vs. AG+GG), and (C) allele (A vs. G). M-H, Mantel-Haenszel; CI, confidence interval.
2) Recessive (AA vs. AG+GG)
Based on our pooled analysis of datasets from 12 studies, involving a total of 16,570 participants, we found that the recessive model of TSHR gene polymorphism (rs179247) (AA vs. AG+GG) is associated with an increased risk of developing GD (OR, 1.65; 95% CI, 1.52 to 1.80; P<0.00001; I2=30%; random-effect model) (Fig. 2B).
3) Alleles (A vs. G)
A meta-analysis of datasets from 13 datasets derived from 11 studies (n=30,884), demonstrated that the A allele of the TSHR (rs179247) gene polymorphism is associated with a higher risk of developing GD compared to the G allele (OR, 1.44; 95% CI, 1.37 to 1.52; P<0.00001; I2=13%; random-effect model) (Fig. 2C).
Additional model
1) AA vs. GG
A meta-analysis including 14 datasets from 12 studies (n=9,106), demonstrated that the AA genotype of the TSHR (rs179247) gene polymorphism is associated with a higher risk of GD than the GG genotype (OR, 2.09; 95% CI, 1.89 to 2.31; P<0.00001; I2=0%; random-effect model) (Supplemental Fig. S1A).
2) AA vs. AG
A meta-analysis involving 14 datasets from 12 studies (n=14,006) showed that the genetic model consisting of the AA genotype of the TSHR (rs179247) gene polymorphism was associated with a higher risk of GD than the AG genotype (OR, 1.54; 95% CI, 1.40 to 1.68; P<0.0001, I2=31%; random-effect model) (Supplemental Fig. S1B).
3) AG vs. GG
A meta-analysis of 14 datasets from 12 studies (n=10,024) showed that the genetic model consisting of the AG genotype of TSHR (rs179247) gene polymorphism was associated with a higher risk of GD than the GG genotype (OR, 1.39; 95% CI, 1.27 to 1.53; P<0.00001; I2=0%; random-effect model) (Supplemental Fig. S1C).
Hashimoto thyroiditis
Classical model
1) Dominant (AA+AG vs. GG)
A pooled analysis of four studies (n=1,083) showed no association between the dominant model of TSHR (rs179247) gene polymorphism (AA+AG vs. GG) and the risk of developing HT (OR, 0.70; 95% CI, 0.40 to 1.24; P=0.23; I2=59%; random-effect model) (Fig. 3A).
Forest plot demonstrating the association between classical genetic models of the relationship between the thyroid-stimulating hormone receptor (TSHR) rs179247 gene polymorphism and the risk of Hashimoto’s thyroiditis: (A) dominant (AA+AG vs. GG), (B) recessive (AA vs. AG+GG), and (C) allele (A vs. G). M-H, Mantel-Haenszel; CI, confidence interval.
2) Recessive (AA vs. AG+GG)
A pooled analysis including four studies (n=1,083) showed no association between the recessive model of the TSHR (rs179247) gene polymorphism (AA vs. AG+GG) and the risk of developing HT (OR, 1.01; 95% CI, 0.71 to 1.43; P=0.96; I2=37%; random-effect model) (Fig. 3B).
3) Alleles (A vs. G)
A pooled analysis of four studies (n=2,156) showed no association between the A versus G allele of the TSHR (rs179247) gene polymorphism and the risk of developing HT (OR, 0.90; 95% CI, 0.70 to 1.15; P=0.41; I2=42%; random-effect model) (Fig. 3C).
Additional model
1) AA vs. GG
A pooled analysis of four studies (n=591) revealed no association between the AA genotype of the TSHR (rs179247) gene polymorphism and the risk of developing HT when compared to the GG genotype (OR, 0.80; 95% CI, 0.40 to 1.60; P=0.53; I2=63%; random-effect model) (Supplemental Fig. S2A).
2) AA vs. AG
A pooled analysis including four studies (n=889) revealed no association between the AA genotype of the TSHR (rs179247) gene polymorphism with the risk of developing HT when compared to the AG genotype (OR, 1.12; 95% CI, 0.77 to 1.62; P= 0.56; I2=36%; random-effect model) (Supplemental Fig. S2B).
3) AG vs. GG
A pooled analysis of four studies (n=686) revealed no association between AG genotype of the TSHR (rs179247) gene polymorphism with the risk of developing HT when compared to the GG genotype (OR, 0.67; 95% CI, 0.38 to 1.19; P=0.18; I2=55%; random-effect model) (Supplemental Fig. S2C).
Meta-regression
Meta-regression was conducted solely for the GD genetic models, as HT did not produce any statistically significant results. The results of the meta-regression analysis, which explored several factors that might influence the relationship between the TSHR (rs179247) gene polymorphism and GD, are presented in Table 3. Factors such as country of origin (with Asia as the reference) (P=0.7361), sample size (P=0.8064), age (P=0.9804), and sex distribution (P=0.9403) did not significantly impact the association between the TSHR (rs179247) gene polymorphism and GD risk in the dominant model (AA+AG vs. GG). Similarly, in the recessive model (AA vs. AG+GG), none of these factors, including country of origin (Asia as reference) (P=0.7408), sample size (P=0.1194), age (P=0.6127), and sex distribution (P=0.9327), significantly influenced the risk of GD. Furthermore, in the allele model (A vs. G) of the TSHR (rs179247) gene polymorphism, the analysis showed that none of the examined factors—country of origin (Asia as reference) (P=0.3731), sample size (P=0.3558), age (P=0.8114), and sex distribution (P=0.8939)—affected GD susceptibility. Lastly, the meta-regression analysis indicated that the relationships of all additional genetic models, including AA vs. GG, AA vs. GA, and AG vs. GG, were not significantly influenced by any of the confounding factors, such as country of origin, sample size, age, and sex distribution.
Results of Meta-Regression for Each Genetic Model of the Relationship between the rs179247 Gene Polymorphism and the Development of Graves’ Disease
Publication bias
Funnel plot analysis was employed to assess publication bias. The analysis revealed relatively symmetrical inverted plots across all genetic models in GD, suggesting an absence of publication bias (Supplemental Fig. S3). However, the current study did not assess publication bias for genetic models in HT, as fewer than 10 studies (only four) were included for each outcome of interest. Therefore, the evaluation of publication bias does not achieve the same level of robustness as it would with more than 10 studies available for analysis [27,28].
DISCUSSION
Our systematic review and meta-analysis indicated that all genetic models of the TSHR (rs179247) gene polymorphism significantly elevate the risk of developing GD. These models encompass the dominant model (AA+AG vs. GG), the recessive model (AA vs. AG+GG), the AA genotype, the AG genotype, and the A allele. Further regression analysis also demonstrated that these associations were not significantly influenced by confounding factors such as country of origin (Asia vs. non-Asia), sample size, age, and sex distribution. Conversely, our meta-analysis did not identify any statistically significant associations between all genetic models of the TSHR (rs179247) gene polymorphism and susceptibility to HT. This suggests that other single-nucleotide polymorphisms (SNPs) or genes besides TSHR may influence HT.
Two potential mechanisms may explain the association between TSHR intron 1 (rs179247) gene polymorphism and the increased risk of GD. The first mechanism involves alternative splicing that leads to the production of soluble TSHR, a process known as peripheral tolerance [29,30]. Additionally, post-translational intramolecular cleavage of the TSHR protein could result in the release of the TSHR A-subunit [29,30]. This process is thought to potentially initiate or exacerbate autoimmunity in GD [29,30]. Empirical evidence indicates that TSHR autoantibodies predominantly target the extracellular A-subunit [29,30]. Moreover, it has been demonstrated that administering the TSHR A-subunit via intramuscular injection in a murine model is essential for inducing TSHR autoantibody production and the subsequent development of hyperthyroidism [29,30]. Three specific types of TSHR are produced by the major transcripts of TSHR: the full-length TSHR (flTSHR), ST4, and ST5 [29,30]. Both ST4 and ST5 include the first 8 exons of flTSHR and an additional ninth exon [29,30]. Intron 8 is divided into two segments that encode this ninth exon, leading to intron retention [29,30]. The study by Brand et al. [15], included in our meta-analysis, analyzed flTSHR, ST4, and ST5 expression in 12 thyroid tissue samples. The findings indicated that ST4 and ST5 expression was higher in individuals with the AA genotype than in those with the GG genotype [15]. The risk allele (A allele) of TSHR SNP (rs179 247AA) was associated with a reduced ratio of flTSHR to ST4 and flTSHR to ST5 [15]. The increased expression of ST4 and ST5 resulted in elevated synthesis of the soluble “A” subunit of TSHR in the peripheral region [15]. This led to the production of thyroid autoantibodies and the development of GD [15,29,30].
The subsequent mechanism involves the regulation of TSHR expression in the thymus, a process known as central tolerance [30,31]. The risk allele (A) leads to reduced TSHR expression in the thymus, which results in decreased elimination of TSHR self-reactive T cells [30,31]. Consequently, the number of TSHR self-reactive T cells increases [30,31]. As a result, germinal centers in the lymph nodes draining the thyroid can produce more TSHR antibodies, triggering the development of GD [30,31]. Colobran highlighted this concept in his research [32]. Carriers of the risk allele (A) at rs179247 exhibited fewer TSHR mRNA transcripts in the thymic glands of non-autoimmune donors who were homozygous compared to carriers of the protective allele (G) [32]. In heterozygous individuals, the TSHR risk allele (A) was present at a lower level than the protective allele (G) [32].
Our meta-analysis results are consistent with the findings of the 2016 meta-analysis by Xiong et al. [33]. Their study established a correlation between the TSHR (rs179247) gene polymorphism and susceptibility to GD [33]. Although both studies reached similar conclusions, there are several important differences between the study by Xiong et al. [33] and our current investigation.
First, Xiong et al. [33] included only eight papers that investigated the rs179247 gene polymorphism. Of these, five studies focused on the rs179247 gene polymorphism in individuals with GD compared to healthy controls, while the remaining three examined the differences between GD patients with ophthalmopathy and those without [33]. Our meta-analysis, in contrast, encompassed 12 studies that explored the rs179247 gene polymorphism in both individuals with GD and healthy populations. The objective was to assess whether a specific SNP in intron 1 of the TSHR gene could influence the risk of developing GD. Including a greater number of studies in our analysis increases the robustness of the evidence produced.
Second, Xiong et al. [33] employed different approaches to determine the dominant and recessive models of the TSHR rs179247 gene polymorphism. In their study, they identified GG+GA vs. AA as the dominant model and GG vs. GA+AA as the recessive model. This classification impacts the conclusions, suggesting that the dominant and recessive models of the TSHR rs179247 gene polymorphism provide protection against GD [33]. When describing the TSHR intron 1 gene, specifically the rs179247 A/G variant with allele A listed before allele G, the correct notation for the dominant model should be AA+AG vs. GG, and for the recessive model, it should be AA vs. AG+GG. Consequently, in our meta-analysis, we adhered to this standard notation, which led to a revised conclusion that both the dominant and recessive models are associated with an increased risk of GD.
Third, our meta-analysis incorporated meta-regression to evaluate the influence of various confounding factors on the outcomes. Further regression analysis indicated that variables such as country of origin, sample size, age, and sex distribution did not significantly affect the association between the TSHR (rs179247) gene polymorphism and the likelihood of developing GD. Additionally, we examined HT alongside GD, as both conditions are categorized as AITDs. This approach differs from the previous study by Xiong et al. [33], which focused solely on GD. However, our findings did not reveal a significant association between the TSHR (rs179247) gene polymorphism and the risk of developing HT.
This investigation has several limitations. First, the research findings are based on case-control studies, which are susceptible to biases such as information bias, selection bias, and the presence of confounding factors. Consequently, our results should be interpreted with caution. Although a Mendelian randomization study is the optimal design for examining the impact of genetic factors on a specific disease, research of this nature is still lacking on the topic of TSHR gene polymorphisms and GD. Second, the studies included in our analysis did not provide sufficient information on goiter size, thyroid function test results, thyroid antibody test results, and environmental factors that could influence the outcomes. As a result, a comprehensive analysis of how these factors interact with genetic factors is not feasible. Incorporating this data would significantly improve our understanding of the complex pathophysiology of GD and HT. Finally, some of the studies we analyzed had small sample sizes—specifically, fewer than 500 individuals. To validate the findings of our study, further research with larger sample sizes that include data on hormonal and environmental factors is necessary.
In conclusion, our systematic review and meta-analysis have identified an association between the TSHR (rs179247) gene polymorphism and an increased risk of developing GD. This elevated risk was consistent across all genetic models tested, including dominant (AA+AG vs. GG), recessive (AA vs. AG+GG), AA genotype, AG genotype, and the A allele of the TSHR (rs179247) gene polymorphism. Further regression analysis indicated that this association is not affected by factors such as country of origin, sample size, age, and sex distribution. However, our analysis did not find a significant association between the TSHR (rs179247) gene polymorphism and susceptibility to HT. Therefore, our findings suggest that rs179247 may be a significant biomarker for predicting the risk of GD, but not HT. Further research is necessary to investigate the role of other SNPs in the TSHR gene or adjacent genes in the development of both GD and HT, as our current study focused solely on one SNP (rs179247). Future studies should also consider examining the gene-environment interactions that may influence the development of AITDs.
Supplementary Material
Supplemental Table S1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Checklist [12]
Supplemental Table S2.
List of Excluded Studies with Their Reasons of Exclusion
Supplemental Fig. S1.
Forest plot that demonstrates the association between additional genetic models of thyroid-stimulating hormone receptor (TSHR) rs179247 gene polymorphism: (A) AA vs. GG, (B) AA vs. AG, and (C) AG vs. GG with the risk of Graves’ disease. M-H, Mantel-Haenszel; CI, confidence interval.
Supplemental Fig. S2.
Forest plot that demonstrates the association between additional genetic models of thyroid-stimulating hormone receptor (TSHR) rs179247 gene polymorphism: (A) AA vs. GG, (B) AA vs. AG, and (C) AG vs. GG with the risk of Hashimoto thyroiditis. M-H, Mantel-Haenszel; CI, confidence interval.
Supplemental Fig. S3.
Funnel plot analysis that demonstrates relatively symmetrical inverted plot for the association between genetic models of thyroid-stimulating hormone receptor (TSHR) rs179247 gene polymorphism: (A) dominant, (B) recessive, (C) allele, (D) AA vs. GG, (E) AA vs. AG, and (F) AG vs. GG with the risk of Graves’ disease. SE, standard error; OR, odds ratio;
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: H.Z., T.I.H. Acquisition, analysis, or interpretation of data: H.Z., T.I.H. Drafting the work or revising: H.Z., T.I.H. Final approval of the manuscript: H.Z., T.I.H.